The Evolution and Implications of the Inosine tRNA Modification

Ever since the legendary publication by Francis Crick in JMB introducing the wobble hypothesis in 1966, inosine has been a permanent part of molecular biology. This review aims to integrate the rich array of novel insights emerging from subsequent research on the adenine-to-inosine modification of tRNA, with an emphasis on the results obtained during the last 5 years. Both the grand panorama of 4 billion years of evolution of life and the medical implications of defects in inosine modification will be reviewed. The most salient insights are that: (1) inosine at position 34 (the first position in the anticodon) is not universally present in the tree of life; (2) in many bacteria just a single homodimeric enzyme (TadA) is responsible for both tRNA inosine modification and mRNA inosine modification; (3) rapid progress is currently being made both in the molecular understanding of the heterodimeric ADAT2/ADAT3 enzyme responsible for inosine modifications in eukaryotes and in experimental capabilities for monitoring both the cytoplasmic tRNA pool and their modifications; (4) for selected tRNAs, inosine modification at position 37 has been demonstrated but this modification remains under-studied; (5) modification of tRNAs known to contain inosine can be incomplete; (6) the GC content of the T-stem is of great importance for wobble behavior, including wobbling behavior of inosine; and (7) the tRNA inosine modification is of direct relevance to human disease. In summary, research on inosine continues to yield important novel insights.